Novel indole-based sigma-2 receptor ligands: synthesis, structure-affinity relationship and antiproliferative activity

We report the synthesis and biological evaluation of a series of indole-based sigma(2) receptor ligands derived from siramesine. In vitro competition binding assays showed that these analogues possessed high to moderate affinity and selectivity for sigma(2) receptors. Structure-affinity relationship analyses of these indole-based sigma(2) receptor ligands were performed. In the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 1a and 1b displayed significant and comparable antiproliferative activity in DU145, MCF7 and C6 cells to siramesine. In cell cycle analyses, compounds 1a, 1b and siramesine were found to induce a G(1) phase cell cycle arrest in DU145 cells using flow cytometry. The combination of 5,6-dimethoxy-isoindoline scaffold and N-(4-fluorophenyl) indole moiety was identified as a new sigma(2) receptor ligand deserving further investigation as an antitumor agent.